1. Field of the Invention
This invention relates to a method of preventing the precipitation of hormone preparations within drug delivery systems that depend on the fluidity of the infusate for proper function. One system of this type is the implantable infusion pump illustrated and described in Blackshear et al U.S. Pat. No. 3,731,681, the disclosure of which is incorporated herein by reference. The addition of specific detergents in low concentrations increases the solubility of the hormone, such as insulin, in water without affecting its biological activity. The detergent solubilizes both native or denatured hormones and inhibits the action of precipitation agents, such as metal ions.
The control of many cellular functions in an organism is via hormones, such as insulin, human growth hormone, glucagon, and the like, secreted in very small amounts by specific glands into the blood stream. These hormones have high affinity for specific sites on or in the membranes of the specific cells. The hormones are typically small proteins with a marginal solubility in blood. The hormone is functionally active in the hydrophobic lipid membrane. A typical hormone deficiency disease is diabetes where the beta cells in the pancreas have been destroyed and the medical treatment is the administration of insulin from animal origins.
Recent studies have suggested that management of blood glucose in insulin dependent diabetics can be improved by administering insulin by pump on a continuous basis, or in pulses several minutes apart, rather than by intermittent injections as is now common practice. One factor limiting the length of time this kind of administration can be maintained is precipitation of insulin in the flow passages of these pumps causing flow stoppage. There is mounting evidence that such improvement of control, if provided on a long-term basis, might inhibit or alleviate the development of diabetic complications such as blindness and kidney failure. Thus, the availability of an agent to maintain the solubility of insulin under those circumstances could potentially have substantial impact on the treatment of diabetes.
The implanted infusion pump of U.S. Pat. No. 3,731,681 has been used successfully to administer heparin for the treatment of blood clotting disorders. Heparin is a highly soluble and very negatively charged molecule. No difficulty was encountered with the metering of this drug using small bore capillary tubes or with the delivery of the drug to the blood stream using a conventional silicone rubber catheter. Over five years of continuous intravenous heparin delivery has been achieved in dogs with this system. Comparable infusion time periods were achieved when sterile water was substituted for heparin. However, when the same pump was used to deliver commercial regular insulin, in standard insulin diluting fluid, the pumps would flow normally for only one to two months. A progressive blockage of the passageways took place with eventual flow stoppage. Often a solid plug of amorphous proteinaceous material was found at the distal end of the small bore capillary, but plugs were found in some cases in the proximal end of the capillary or in the larger bore cannula. These plugs were dissimilar from thrombus plugs which sometimes occurred at the cannula tip.
The major difficulty in the administration of insulin chronically by implanted infusion pump comes from the nature of proteins and the very dilute solution needed. Since insulin delivered by injection is normally administered rapidly (either intramuscularly or intravenously), there is no problem with any possible precipitation reaction with the blood. When the insulin is given chronically, the flow rate by necessity becomes low. This permits insulin and blood components to react in and plug the end of the catheter.
Others using chronic insulin delivery systems have experienced similar problems. Long-term functioning of insulin delivery systems cannot be maintained using standard insulin preparations. The initial approach was to solve the problem of plugging by hardware changes. When these proved to be ineffective, the next approach was to alter the solution used to solubilize the insulin.
2. Prior Art
F. Bischoff (The influence of sodium lauryl sulfate on the biologic response to the gonadatropins and to insulin. Amer. J. of Physiology 145: 123-129, 1945) discloses that if a solution of sodium lauryl sulfate (sodium dodecyl sulfate) (SDS) and insulin is diluted to 0.12% SDS before delivery, no loss in activity of the insulin was found. Although the insulin is denatured by high SDS concentration (1 to 5%) and would be partially destroyed in the blood stream, the insulin can return to its natural state rapidly when diluted and function normally. SDS was not useful as a solubilizing agent for insulin when given by conventional subcutaneous injections since the insulin is partially destroyed before it can be absorbed into the blood stream.
It is known that the binding of detergents to proteins occurs readily. The binding ratio for the common anionic detergent sodium dodecyl sulfate has been determined for proteins to be: 0.4 gm-1.4 gm SDS/gm protein (Rosalind Pitt-Rivers and F.S.A. Impiombato. The binding of sodium dodecyl sulfate to various proteins. Biochem Journal 109:825-830, 1968, and Jacqueline Reynolds and Charles Tanford. Binding of dodecyl sulphate to proteins at high binding ratios. Proceedings of the National Academy of Sciences. 66:1002-1007, 1970).
SDS is also reported to disrupt or prevent the formation of antigen-antibody complexes (Louis Qualtiere, Amil Anderson, and Paul Meyers. Effects of ionic and nonionic detergents on antigen-antibody reactions. J. of Immunology 119:1645-1651, 1977).
Bray et al U.S. Pat. No. 3,000,874 discloses that, although it is not used as a drug by itself, SDS is used to enhance absorption of other drugs.